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Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #76: Insulin Actions in Vivo: Glucose Metabolism Part 2 of 9

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #76: Insulin Actions in Vivo: Glucose Metabolism Part 2 of 9

Glucose metabolism

Introduction   

Any given concentration of glucose in plasma (and in the space in equilibrium with plasma) is the result of simultaneous release of glucose into the circulation and uptake of glucose from the bloodstream into cells. Whenever plasma glucose concentration is stable, the concurrent rates of its release and overall uptake must be equal. Glucose turnover (TR) is this rate of constant flux through its system. Accepted terminology refers to stationary conditions of glucose concentrations and flux rate as the “steady state,” with the understanding that any physiologic steady state is only an approximation of the true, ideal steady state. Furthermore, the “glucose system” refers to the whole space or volume into which glucose is present as free glucose, regardless of how many compartments this system consists of, where they are physically located in the body, and how they are interconnected. Finally, the reference pool for glucose kinetics customarily is the plasma (or whole blood), for in most clinical or experimental circumstances the plasma is the only site accessible for sampling. When the plasma glucose concentration changes over time, one rate of glucose flux (entry or removal) is being exceeded by the other. Under these non-steady-state conditions, the glucose rates of entry and removal are conventionally termed rate of appearance (Ra) and disappearance (Rd), respectively. The glucose system is strongly homeostatic with respect to glucose levels, in that the normal variations in human plasma glucose concentration throughout a day of life are confined within a surprisingly narrow range. It should be recalled that glucosuria is called upon whenever glycemia exceeds the renal threshold, ∼180 mg dL−1 , as if a safety measure had been set to cope with emergency when metabolic control fails. These considerations alone indicate that the body does not tolerate either hypoglycemia or hyperglycemia. For the former, the obligate dependence of brain function on the use of glucose as fuel classically has been offered as a rational explanation. For hyperglycemia, the evidence — and hence the concept — that high glucose levels, if not immediately life-threatening, are nonetheless intolerable to bodily functions, is more recent but no less compelling, and currently goes under the name of “glucose toxicity” (see Chapter 27).

Method

Under conditions of an overnight fast, the liver accounts for ∼80% of glucose production with the remaining ∼20% coming from the kidney [12,13]. Placing catheters across the splanchnic bed (one in a hepatic vein and another in any artery) and measuring splanchnic blood flow (e.g. by infusing a dye, such as indocyanine green, that is only cleared by the hepatocyte) allows the measurement of glucose turnover as the product of A-V difference and blood flow (Figure 14.1). Chapter14Fig14.1However, the liver and extrahepatic splanchnic tissues (gut, pancreas, spleen, etc.) also take up glucose; the application of the Fick principle allows one to estimate the net balance between glucose uptake and release in the splanchnic area, not the total rate of glucose turnover (Figure 14.1). One must resort to glucose tracers, such as radioactive (e.g. 3H-glucose or 14 C-glucose) or stable (e.g. 2 H-glucose or 13 C-glucose) isotopes of glucose. The kidney, like the liver, also simultaneously takes up and releases glucose. By combining tracers and renal vein catheterization with measurement of renal plasma flow (using para-aminohippurate), one can quantitate the bidirectional flux of glucose across the kidney, similar to that described across the splanchnic bed. Details of the tracer technique as applied to glucose turnover measurement can be found in several reviews and treatises [14,15].

A tracer can be administrated as a pulse injection or con- stant intravenous infusion or combination thereof. Under steady-state conditions applying to both tracee (i.e., glucose) and tracer, glucose turnover rate is simply given by the ratio of the tracer infusion rate (IR) to the equilibrium plasma glucose specific activity (SA = tracer/tracee concentration). Equilibrium is the time (usually 2 – 3 h after starting the tracer infusion) when unchanging plasma tracer concentrations indicate that glucose specific activity has become uniform throughout its distribution space. This formula, IR/SA, is not based on any assumptions other than the attainment of equilibrium. When non-steady-state conditions prevail, this approach cannot be used because either the tracer or the tracee concentration (or both) change over the period of measurement. Unfortunately, in the patient with diabetes the glucose system is unsteady for most of the time, precisely because homeostasis has been lost. However, practicable ways around the problem do exist [16] and the reader is referred to several reviews of the topic [14,15].

As discussed earlier, glucose tracers are useful in the study of regional metabolism in two respects:

  1. For organs in which glucose uptake and release occur simultaneously (typically, the liver and kidney) the AV difference for the tracer offers a measure of absolute uptake (for the tracer is not produced by the organ), while absolute release can be calculated as the difference between net balance (as measured by the Fick principle) and uptake. If A* and V* and A and V are the arterial and venous tracer and tracee concentrations, respectively, and F is the blood flow, the absolute glucose uptake rate is (GU) = (A*-V*)/A* × A × F and the net balance is (NB) = (AV) × F. The rate of glucose production is (GP)=NB – GU=F×A×(V* /A*-V/A).
  2. As tracer glucose is metabolized, its label will appear in one or more degradation products (P*). For any degradation product, the ratio of its labeled moiety to the specific activity of glucose (i.e., P* × [A*/A]−1 ) is the amount of that product generated from glucose (in units of concentration). For example, measuring 14 C-lactate and 14 C-carbon dioxide during the infusion of 14C-glucose makes it possible to estimate the amounts of glucose that were glycolyzed and completely oxidized, respectively. If, then, the kinetics of precursor and product are separately determined, all of these precursor – product relationships can be converted into fluxes of interconversion, regionally as well as at the whole-body level.

An important concept in kinetics and physiology is that of glucose clearance. When referred to the plasma volume, glucose clearance is the volume of plasma that is completely cleared of glucose per unit time. Glucose clearance (CR) is related to glucose turnover rate as follows: TR = CR × G (where G is the glucose concentration in the same pool, plasma or blood, arterial or venous, in which the tracer concentration was determined). At the level of an organ that only consumes glucose — that is, in which U = F × (A-V) (Figure 14.1) — glucose clearance is also given by U/A or [F × (A-V)/A]. The latter formula calculates net glucose clearance in organs in which there is simultaneous glucose uptake and release. As the ratio (A-V)/A is the extraction ratio (or fractional extraction) of glucose, the product [F × (A-V)/A] is the fraction of the flow to an organ that is totally cleared of glucose at any glucose concentration. Thus, the clearance rate is a measure of the efficiency of glucose removal regardless of glycemia. As such, it “feels” the impact of specific stimuli (e.g. insulin) independently of the mass action of glucose. It is important in this context to bear in mind that the tracer method actually measures glucose clearance (as the ratio of the tracer infusion rate to the equilibrium plasma tracer concentration), and derives glucose turnover rate as the product of clearance and glycemia.

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